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WO1995011689A1 - Utilisation d'inhibiteurs de la dipeptidylaminopeptidase pour bloquer l'entree du vih dans des cellules - Google Patents

Utilisation d'inhibiteurs de la dipeptidylaminopeptidase pour bloquer l'entree du vih dans des cellules Download PDF

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WO1995011689A1
WO1995011689A1 PCT/US1993/010423 US9310423W WO9511689A1 WO 1995011689 A1 WO1995011689 A1 WO 1995011689A1 US 9310423 W US9310423 W US 9310423W WO 9511689 A1 WO9511689 A1 WO 9511689A1
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group
alkyl
compound
independently
formula
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William W. Bachovchin
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Trustees Of Tufts College
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides

Definitions

  • DP IV dipeptidyl amino peptidase type IV
  • DP IV is a serine protease present in many microbes, mammalian cells and tissues, for example, renal tubule cells, intestinal epithelium, and blood plasma. It is also present on the surface of CD-4+ and some CD-8+ T-cells, and in low amounts in the central nervous system. It is thought to be involved in the regulation of the immune response; occurrence of DP IV on a cell surface is associated with the ability of cells to produce interleukin 2 (IL-2) .
  • DP IV is also referred to as DAP IV or DPP IV; it is assigned EC number 3.4.14.5.
  • DP IV Three different inhibitors of DP IV are known.
  • One of these is a suicide inhibitor: N-Ala-Pro-O- (nitrobenzyl-)hydroxylamine. (The standard three letter amino acid codes are used in this application; 0 represents oxygen.)
  • Another is a competitive inhibitor: e-(4-nitro)benzoxycarbonyl-Lys-Pro.
  • the third is a polyclonal rabbit anti-porcine kidney DP IV immunoglobuli .
  • DP IV The enzymatic activity of DP IV involves cleaving of a dipeptide from the free amino terminus of a polypeptide.
  • DP IV has a preference for cleaving after a proline, i.e., a proline in the penultimate position from the amino terminus. A free amino terminus is required; thus, DP IV is a po ⁇ tproline cleaving enzyme with a specificity for removing an N-terminal W-Pro dipeptide
  • DP IV also will remove a W'-Ala dipeptide from an amino terminus of a polypeptide when W is an amino acid with a bulky side group, e.g., tyrosine.
  • This invention concerns potent inhibitors of the enzymatic activity of DP IV.
  • an ⁇ -amino boronic acid analog of proline boroPro is used to designate one such analog which has the carboxyl group of proline replaced with a B(OH) 2 group, where (0H) 2 represents two hydrogen groups and B represents boron) is bonded to an amino acid to form a dipeptide with boroPro as the C-terminal residue.
  • Dipeptides having the boroPro moiety are unstable; thus, inhibitors used in the invention have at least two other amino acids.
  • the structure of these inhibitors is X-Pro-Y-boroPro where X and Y are chosen from any amino acid (including proline) .
  • This tetrapeptide may be lengthened at its N-terminus by addition of one or more dipeptides, each dipeptide having the general formula Z-Pro or Z-ala, where each Z independently is any amino acid (including proline) .
  • This general structure is defined in more detail below.
  • These inhibitors function as inhibitors of DP IV because each dipeptide portion is a substrate for DP IV and the final product of the reaction of an inhibitor with DP IV is the dipeptide inhibitor Y-boroPro.
  • the invention features use of an inhibitory compound having the structure: Group I - Group II.
  • Group I has the structure:
  • H represents a hydrogen
  • C represents a carbon
  • O represents an oxygen
  • N represents a nitrogen
  • each R independently, is chosen from the group consisting of the R groups of amino acid, including proline
  • each broken line independently, represents a bond to an H or a bond to one R group, and each H' represents that bond or a hydrogen
  • p is an integer between 0 and 4 inclusive in the preparation of a medicament for administration to a human patient who is infected with HIV, but who is not yet suffering from AIDS, as defined by The Center for Disease Control, Atlanta, Georgia, wherein the compound blocks entry of HIV into uninfected CD26+ cells of the patient by blocking CD26.
  • Group I has the structure:
  • each G2 and G3 independently is H or CI - 3 (one to three carbon atoms) alkyl, Gl is NH3 (H3 represents three hydrogens),
  • G5 and G6 can be NH, H, or CI - 3 alkyl or alkenyl with one or more carbons substituted with a nitrogen.
  • Gl bears a charge
  • Gl and Group II do not form a covalently bonded ring structure at pH 7.0.
  • Group I may also have the structure:
  • Group I may also include a five membered unsaturated ring having two nitrogen atoms, e.g., an imidazole ring.
  • Group II has the structure:
  • T is a group of the formula:
  • each Dl and D2 independently, is a hydroxyl group or a group which is capable of being hydrolysed to a hydroxyl group in aqueous solution at physiological pH; a group of the formula:
  • G is either H, fluorine (F) or an alkyl group containing 1 to 20 carbon atoms and optional heteroatoms which can be N, S (sulfur) , or 0; or a phosphonate group of the formula:
  • each J independently, is O-alkyl, N-alkyl, or alkyl.
  • Each O-alkyl, N-alkyl or alkyl includes 1 - 20 carbon atoms and, optionally, heteroatoms which can be N, S, or 0.
  • T is generally able to form a complex with the catalytic site of a DP IV.
  • Y is R3 - C - R4, R3. - C - C - R6, or
  • each Rl, R2, R3, R4, R5, R6, R7, and R8, separately is a group which does not significantly interfere with site specific recognition of the inhibitory compound by DP IV, and allows a complex to be formed with DP IV.
  • T is a boronate group, a phosphonate group or a trifluoroalkyl ketone group; each Rl - R8 is H; each Rl and R2 is H, and each Y is the CH 2 - CH 2 ; each R is independently chosen from the R group of proline and alanine; the inhibitory compound has a binding or dissociation constant to DP IV of at least 10 ⁇ 9 M, 10" 8 M or even 10 "7 M; the inhibitory compound is admixed with a pharmaceutically acceptable carrier substance; and each Dl and D2, independently, F, or Dl and D2 together are a ring containing 1 to 20 carbon
  • Preferred compounds have the formula
  • each D 1 and D 2 independently, is a hydroxyl group or a group which is capable of being hydrolyzed to a hydroxyl group in aqueous solution at physiological pH; and X comprises an amino acid or a peptide which mimics the site of a substrate recognized by a post prolyl cleaving enzyme. It is also preferred that the amino acid derived moieties of the inhibitor be entirely L-isomers, and that the carbon atom bonded to the boron atom also be of the L-configuration. Thus, preferred inhibitors have the structure
  • m is an integer betwen 0 and 10, inclusive;
  • a and A 7 are L-amino acid residues such that the A in each repeating bracketed unit can be a different amino acid residue;
  • the C bonded to B is in the L-configuration;
  • the bonds between A and N, A and C, and between A and N are peptide bonds;
  • each X 1 and X 2 is, independently, a hydroxyl group or a group capable of being hydrolysed to a hydroxyl group at physiological pH.
  • the invention is based on the ability of the inhibitors to block CD26 and thus block entry of HIV into CD26-bearing cells.
  • the inhibitors are administered (preferably orally, in tablet, capsule, or liquid form) to an HIV-infected patient who does not yet exhibit the symptoms of full-blown AIDS, to inhibit entry of virus into healthy, uninfected cells of the patient, in particular, CD4 + lymphocytes.
  • the patient has a CD4 + count of at least 200, and more preferably at least 400, at the time of administration of the inhibitor.
  • the inhibitors treat pre-symptomatic HIV- infected patients not by neutralizing virus, as is the case for some AIDS therapies, but by blocking viral entry into the cells.
  • Unit dosage of the inhibitor is preferably between 10 and 500, more preferably between 20 and 100, and most preferably between 20 and 80 ⁇ g/kg body weight, so that several unit doses in pill, tablet, or capsule form, for use in a 68 kg patient will be made available; these unit dose formulations will contain 500, 1500, 5000, and 30,000 ⁇ g of inhibitor.
  • These unit dose formulated pills, capsules, or tablets will preferably be in a sustained release form, and will be administered orally on a daily, every other day, or once-per week basis, to provide a daily dosage to the patient in the ranges recited above.
  • Liquid unit dosage formulations for oral or, less preferably, injectable administration can be employed as well.
  • Figure 1 is a diagrammatic representation of several inhibitors.
  • Figure 2 is a diagrammatic representation of the synthesis of a boro proline compound. Structure
  • inhibitory compounds useful in the invention have the general structure recited in the Summary of the Invention above. Examples of preferred structures are those referred to as preferred embodiments above.
  • the structure of the inhibitory compounds is such that at least a portion of the amino acid sequence near the cleavage site of a DP IV substrate is duplicated, or nearly duplicated.
  • the choice of amino acid sequence affects the ability of the inhibitory compound to block CD26.
  • Inhibitory compounds which can complex with DP IV can also block CD26, and thus are useful in the invention. Specificity is determined in a similar fashion, by testing the CD26 blocking effect of a particular inhibitory compound using standard techniques.
  • the inhibitory compounds preferably block CD26 and do not inhibit enzymes necessary for normal cell functions.
  • the inhibitory compounds include a group (T) which causes the inhibitory compound to complex with DP IV, not only in a competitive fashion, but in a chemically reactive manner to form a strong bond between the inhibitory compound and DP IV.
  • This group thus acts to bind the inhibitory compound to DP IV, and increases the inhibitory binding constant (Ki) of the inhibitory compound.
  • groups include boronates, fluoroalkyl ketones and phosphoramidates (of the formulae given in the Summary above) . These groups are covalently bonded to the prolyl residue of the compound, as in the above formula.
  • the starting compound I is prepared essentially by the procedure of Matteson et al., 3 Or ⁇ anometallics 1284, 1984, except that a pinacol ester is substituted for the pinanediol ester.
  • Similar compounds such as boropipecolic acid and 2-azetodine boronic acid can be prepared by making the appropriate selection of starting material to yield the pentyl and propyl analogs of compound I.
  • CI can be substituted for Br in the formula, and other diol protecting groups can be substituted for pinacol in the formula, e.g., 2,3-butanediol and alpha-pinanediol.
  • Compound II is prepared by reacting compound I with [ (CH 3 )0 3 Si] 2 N-Li+. In this reaction hexamethyldisilazane is dissolved in tetrahydrofuran and an equivalent of n-butyllithium added at -78°C. After warming to room temperature (20°C) and cooling to -78°C an equivalent of compound I is added in tetrahydrofuran. The mixture is allowed to slowly come to room temperature and to stir overnight. The alpha-bis[trimethylsilane]- protected amine is isolated by evaporating solvent and adding hexane under anhydrous conditions. Insoluble residue is removed by filtration under a nitrogen blanket, yielding a hexane solution of compound II.
  • the boroProline esters can also be obtained by treatment of the reaction mixture obtained in the preparation of compound II with anhydrous acid to yield l-amino-4-bromobutyl boronate pinacol as a salt. Cyclization occurs after neutralizing the salt with base and heating the reaction.
  • Example 1 Preparation of boroProline-pinacol
  • the intermediate, 4-Bromo-l-chlorobutyl boronate pinacol was prepared by the method in Matteson et al., Organometallics. (3): 1284-1288 (1984), except that conditions were modified for large scale preparations and - li ⁇ the pinacol was substituted for the pinanedoil protecting group.
  • 3-bromopropyl boronate pinacol was prepared by hydrogenboronation of allyl bromide (173 ml, 2.00 moles) with catechol borane (240 ml, 2.00 moles). Catechol borane was added to allyl bromide and the reaction heated for 4 hours at 100°C under a nitrogen atmosphere. The product, 3-bromopropyl bornate catechol (bp 95-102°C, 0.25 mm), was isolated in a yield of 49% by distillation.
  • the catechol ester (124 g, 0.52 moles) was transesterified with pinacol (61.5 g, 0.52 moles) by mixing the component in 50 ml of THF and allowing them to stir for 0.5 hours at 0°C and 0.5 hours at room temperature. Solvent was removed by evaporation and 250 ml of hexane added. Catechol was removed as a crystalline solid. Quantitative removal was achieved by successive dilution to 500 ml and to 1000 ml with hexane and removing crystals at each dilution. Hexane was evaporated and the product distilled to yield 177 g (bp 60 - 64°C, 0.35 mm) .
  • 4-Bromo-l-chlorobutyl boronate pinacol was prepared by homologation of the corresponding propyl boronate.
  • Methylene chloride 50.54 ml, 0.713 moles
  • 1.54 N n-butyllithium in hexane 480 ml, 0.780 moles
  • 3-Bromopropyl boronate pinacol 178 g, 0.713 moles
  • Zinc chloride (54.4 g, 0.392 moles) was dissolved in 250 ml of THG, cooled to 0°C, and added to the reaction mixture in several portions. The reaction was allowed to slowly warm to room temperature and to stir overnight. Solvent was evaporated and the residue dissolved in hexane (l liter) and washed with water (1 liter) . Insoluble material was discarded. After drying over anhydrous magnesium sulfate and filtering, solvent was evaporated. The product was distilled to yield 147 g (bp 110 - 112°C, 0.200 mm) .
  • N-Trimethylsilyl-boroProline pinacol was prepared first by dissolving hexamethyldisilizane (20.0 g, 80.0 mmoles) in 30 ml of THF, cooling the solution to -78°C, and adding 1.62 N n-butyllithium in hexane (49.4 ml, 80.0 mmoles) . The solution was allowed to slowly warm to room temperature. It was recooled to -78°C and 4-bromo-l- chlorobutyl boronate pinacol (23.9 g, 80.0 mmoles) added in 20 ml of THF. The mixture was allowed to slowly warm to room temperature and to stir overnight.
  • H-boroProline-pinacol.HCl was prepared by cooling N-trimethylsilyl-boroProline-pinacol (16.0 g, 61.7 mmoles) to -78°C and adding 4 N HCL:dioxane (46 ml, 185 mmoles) . The mixture was stirred 30 minutes at -78°C and 1 hour at room temperature. Solvent was evaporated and the residue triturated with ether to yield a solid. The crude product was dissolved in chloroform and insoluble material removed by filtration. The solution was evaporated and the product crystallized from ethyl acetate to yield 11.1 g of the desired product (mp 156.5 - 157°C) .
  • the mixed anhydride procedure of Anderson et al., J. Am. Chem. Soc.. .89:5012 (1984) is preferred for peptide coupling.
  • the mixed anhydride of an N-protected amino acid or a peptide varying in length from a dipeptide to tetrapeptide is prepared by dissolving the peptide in tetrahydrofuran and adding one equivalent of N-methylmorpholine. The solution is cooled to -20°C and an equivalent of isobutyl chloroformate is added. After 5 minutes, this mixture and one equivalent of triethylamine (or other sterically hindered base) are added to a solution of H-boroPro- pinacol dissolved in either cold chloroform or tetrahydrofuran.
  • reaction mixture is routinely stirred for one hour at -20°C and 1 - 2 hours at room temperature (20°C) .
  • Solvent is removed by evaporation, and the residue is dissolved in ethyl acetate.
  • the organic solution is washed with 0.20 N hydrochloric acid, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
  • the organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated.
  • Products are purified by either silica gel chromatography or gel permeation chromatography using SephadexTM LH-20 and methanol as a solvent.
  • pinacol protecting group can be removed .in situ by preincubation in phosphate buffer prior to running biological experiments; Kettner et al., J. Biol. Chem. 259: 15106- 15114 (1984) .
  • Several other methods are also applicable for removing pinacol groups from peptides including boroProline and characterizing the final product.
  • the peptide can be treated with diethanolamine to yield the corresponding diethanolamine boronic acid ester, which can be readily hydrolyzed by treatment with aqueous acid or a sulfonic acid substituted polystyrene resin as described in Kettner et al., jld.
  • Both pinacol and pinanediol protecting groups can be removed by treating with BC13 in methylene chloride as described by Kinder et al., J. Med. Chem. , 28: 1917.
  • the free boronic acid can be converted to the difluoroboron derivative (-BF2) by treatment with aqueous HF as described by Kinder et al., id.
  • different ester groups can be introduced by reacting the free boronic acid with various di-hydroxy compounds (for example, those containing heteroatoms such as S or N) in an inert solvent.
  • Example 2 H-Ala-boroPro Boc-Ala-boroPro was prepared by mixed anhydride coupling of the N-Boc-protected alanine and H-boroPro prepared as described above. H-Ala-boroPro was prepared by removal of the Boc protecting group at 0°C in 3.5 molar excess of 4 N HCl-dioxane. The coupling and deblocking reactions were performed by standard chemical reaction. Ala-boroPro has a Ki for DP IV of -1 x 10 ⁇ 9 M. Boc-blocked Ala-boroPro has no affinity for DP IV.
  • the two diastereomers of H-Ala-boroPro-pinacol can be partially separated by silica gel chromatography with 20% methanol in ethyl acetate as eluant.
  • the early fraction appears by NMR analysis to be 95% enriched in one isomer. Because this fraction has more inhibitory power against DP IV than later fractions (at equal concentrations) it is probably enriched in the L-boroPro isomer.
  • H-Ala-boroPro as an inhibitor for DP IV is that it decomposes in aqueous, solution at neutral pH and room temperature (20-25°C) with a half-life of around 0.5 hour.
  • Many dipeptide derivatives with a free N terminal amino group and a functional group (such as a difluoro ethyl ketone) on the C-terminus are similarly unstable due to intramolecular reaction.
  • a six member ring is formed between the amino and C-terminal functional groups and undergoes subsequent further reaction, such as hydrolysis.
  • DP IV bound inhibitor is more stable, consistent with the hypothesis that decomposition is due to an intramolecular reaction.
  • H-Pro-boroPro is more stable than H-Ala-boroPro.
  • the Ki of H-Pro-boroPro for DP IV is about 1 x 10" 8 M, and it decomposes in aqueous solution at room temperature (20 - 25°C) with a half life of about 1.5 hours.
  • the affinity of H-Pro-boroPro is about 10-fold less than that of H-Ala-boroPro , the increased stability is advantageous.
  • inhibitory compounds of the invention are formed as tetrapeptides or longer peptides as shown in the general formula above. These inhibitory compounds are substrates for DP IV yielding the dipeptide inhibitor -boroPro.
  • tetrapeptide boronic acids are generally stable and can be administered by any standard procedure to act as a substrate for DP IV and then as a source of a potent DP IV inhibitor.
  • the advantages of such tetrapeptides is that inhibitor is released only in the vicinity of active DP IV.
  • These tetrapeptide boronic acids can be made by the method of mixed anhydride coupling by one of ordinary skill in the art, e.g., Mattason, Or ⁇ anametallics 2:1284 to 1288, 1984. Test Systems
  • the following are examples of systems by which the inhibitory activity of the above described inhibitory compounds can be tested on DP IV. As an example H-Ala- boroPro is used to test each of these systems.
  • Inhibitory compounds can be tested by simply substituting them for H-Ala-boroPro.
  • DP IV is purified from pig kidney cortex by the method of Barth et al., Acta Biol. Med. Germ. (1974) 32:157, and Wolf et al., Acta Biol. Med. Germ. (1978) 37:409, and from human placenta by the method of Puschel et al., E. Eur. J. Biochem. (1982) 126:359.
  • H-Ala- boroPro inhibits both enzymes with a Ki of -1.0 x 10 ⁇ 9 M.
  • Human Peripheral Blood Mononuclear Cells H-Ala-boroPro was tested for its influence on PHA- induced proliferation of human peripheral blood mononuclear cells.
  • Human peripheral blood mono-nuclear cells were obtained from healthy human donors by Ficoll- Hypaque density gradient centrifugation. The cells are washed three times in RPMI 1640 medium and resuspended to a concentration of a 1 x 10 6 in RPMI. 10% human serum was used as necessary.
  • MNC cells [Ford, W.L. in Handbook of Experimental Immunology edit, by. : D.M. Weir. Blackwell Scientific Publications, Oxford, 1978. p. 23.6] (5 x 10 3 ) were distributed into wells of round-bottom microtitre plates (Nunc) and incubated in the presence or absence of various dilutions of antigen, mitogen, lymphokine or other agent of interest. Cells were cultured in an atmosphere of 5% C0 2 in air for 72 hours after which 3 H-Thymidine (0.5 uCl/well; 2.0 Ci/mM ⁇ p.act., New England Nuclear) was added 6 hours before termination of culture.
  • 3 H-Thymidine 0.5 uCl/well; 2.0 Ci/mM ⁇ p.act., New England Nuclear
  • the cells were harvested with a multiple automatic harvester, and 3 H-thymidine incorporation assessed by liquid scintillation counting. 3 H thymidine incorporation was determined relative to control values in the absence of inhibitor. Inhibitor was added to give a final concentration of 1 x 10 "4 M, but lower concentrations can be used.
  • Other embodiments are within the following claims.
  • other inhibitors can be created which mimic the structure of Ala-boroPro. Examples of such inhibitors are shown in Fig. 2 and include Ala-boroPro. These inhibitors generally have a boroPro group, or its equivalent, described above in the Summary of the Invention, and a positively charged amine group. The inhibitors are designed so that minimal interaction of the amine and boroPro groups occurs, and thus no cyclic structure is formed a pH 7.0. These inhibitors interact and/or bind with DPIV.

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Abstract

L'invention concerne des inhibiteurs de la dipeptidylaminopeptidase de type IV répondant à la formule générale: X-Pro-Y-Boropro, dans laquelle X et Y représentent chacun un aminoacide quelconque (y compris la proline).
PCT/US1993/010423 1993-10-29 1993-10-29 Utilisation d'inhibiteurs de la dipeptidylaminopeptidase pour bloquer l'entree du vih dans des cellules WO1995011689A1 (fr)

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Cited By (44)

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WO1999025719A1 (fr) * 1997-11-18 1999-05-27 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Substance physiologiquement active, la sulphostine, procede de fabrication et utilisation
US5965532A (en) * 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
WO1999056753A1 (fr) * 1998-05-04 1999-11-11 Point Therapeutics, Inc. Stimulation hematopoietique
WO1999067279A1 (fr) * 1998-06-24 1999-12-29 Probiodrug Gesellschaft für Arzneimittelforschung mbH Composes d'inhibiteurs instables de la dipeptidylpeptidase iv
US6011155A (en) * 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
WO2000010549A1 (fr) * 1998-08-21 2000-03-02 Point Therapeutics, Inc. Regulation de l'activite de substrat
US6100234A (en) * 1997-05-07 2000-08-08 Tufts University Treatment of HIV
WO2000047219A2 (fr) 1999-02-10 2000-08-17 Ontogeny, Inc. Procedes et reactifs pour traiter des troubles metaboliques du glucose
US6110949A (en) * 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6166063A (en) * 1998-12-10 2000-12-26 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6172081B1 (en) 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6258597B1 (en) 1997-09-29 2001-07-10 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US6303661B1 (en) 1996-04-25 2001-10-16 Probiodrug Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals
US6319893B1 (en) 1998-07-31 2001-11-20 Probiodrug Raising blood sugar level in hypoglycemic mammals by administering inhibitors of dipeptidyl peptidase IV
US6355614B1 (en) 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
US6500804B2 (en) 2000-03-31 2002-12-31 Probiodrug Ag Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US6548481B1 (en) 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US6559314B2 (en) 1999-06-10 2003-05-06 Probiodrug Ag Method for the production of thiazolidin
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6692753B2 (en) 1997-05-07 2004-02-17 Trustees Of Tufts College Potentiation of the immune response
RU2226533C2 (ru) * 1998-06-24 2004-04-10 Пробиодруг Аг Пролекарства ингибиторов дипептидилпептидазы iv
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
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US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
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US6946480B2 (en) 2002-02-28 2005-09-20 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
US6949515B2 (en) 1999-08-24 2005-09-27 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US6979697B1 (en) 1998-08-21 2005-12-27 Point Therapeutics, Inc. Regulation of substrate activity
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7132104B1 (en) 2000-10-27 2006-11-07 Probiodrug Ag Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
EP1743676A1 (fr) * 2003-11-12 2007-01-17 Phenomix Corporation Dérivés d'acide boronique hétérocycliques, inhibiteurs de dipeptidyl peptidase IV
EP1469873A4 (fr) * 2001-11-26 2007-10-03 Tufts College Inhibiteurs peptidomimetiques d'enzymes de clivage post-proline
US7317109B2 (en) 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
WO2007100374A3 (fr) * 2005-12-19 2008-11-13 Tufts College Inhibiteurs legers de proteases et leurs pro-formes legeres
US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
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US7608577B2 (en) 2001-10-12 2009-10-27 Osi Pharmaceuticals, Inc. Peptidyl ketones as inhibitors of DPIV
US7767828B2 (en) 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7825139B2 (en) 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US8431531B2 (en) 2005-11-30 2013-04-30 Campina Nederland Holding B.V. Methods for stimulating glucagon-like peptide-1(GLP-1) secretion and treatments comprising same
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US7825139B2 (en) 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US8431531B2 (en) 2005-11-30 2013-04-30 Campina Nederland Holding B.V. Methods for stimulating glucagon-like peptide-1(GLP-1) secretion and treatments comprising same
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